Prognostic value of 99mTc-ECD brain perfusion SPECT in patients with atrial fibrillation and dementia
Patients with atrial fibrillation (AF) and dementia experience reduced quality of life and increased mortality. Technetium 99m ECD brain perfusion single-photon emission computed tomography (99mTc-ECD brain perfusion SPECT) is a beneficial modality for diagnosing dementia and identifying high-risk patients with mild cognitive impairment. The aim of this study was to evaluate the prognostic value of brain perfusion using 99mTc-ECD SPECT in patients with AF and dementia.
Of a total of 405 consecutive patients diagnosed with AF as cardiac outpatients with dementia using the Mini-Mental State Examination by neurologists or psychiatrists, we identified 170 patients (81 ± 10 years) who underwent 99mTc-ECD brain perfusion SPECT. Of them, 73, 73, and 24 were diagnosed with Alzheimer’s dementia (AD), vascular dementia (VD), and non-specified dementia, respectively. A multivariable Cox model was used to assess if higher Z-score by 99mTc-ECD brain perfusion SPECT and clinical parameters were associated with major adverse cardiovascular events (MACE) including cardiac death, myocardial infarction, hospitalization for heart failure, and stroke.
During a mean follow-up of 1258 ± 1044 days, 62 MACE occurred. There was no significant difference in MACE between AD and VD (33%, vs. 44%, p = 0.153). The multivariable Cox model confirmed that the higher Z-score of temporo-parieto-occipital lobe was associated with increased MACE compared to the lower group (HR 2.521, 95% CI 1.465–4.337, p < 0.001).
This study demonstrated that decreased cerebral blood flow in the temporo-parieto-occipital lobe could be a potential prognostic value in patients with both AF and dementia.
KeywordsAtrial fibrillation Dementia 99mTc-ECD brain perfusion SPECT Prognosis
Angiotensin converting enzyme inhibitor
Angiotensin II receptor blocker
The area under the curve
Body mass index
Brain natriuretic peptide
Chronic kidney disease
Estimated glomerular filtration rate
The easy Z-score imaging system
Left atrium dimension
Left ventricular ejection fraction
Major adverse cardiac events
Mini-Mental State Examination
Receiver operating characteristic
- 99mTc-ECD brain perfusion SPECT
Technetium 99m ECD brain perfusion single-photon emission computed tomography
Z-score of temporo-parieto-occipital lobe
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it results in reduced quality of life, functional status and cardiac performance . AF is a well-recognized risk factor for cardiovascular disease as well as cerebrovascular disease . It is reported that the prevalence of AF and cognitive disorders is increasing as the older population increases . Patients with cognitive disorders also experience a lower quality of life and increased mortality [3, 4]. Technetium 99m ECD brain perfusion single-photon emission computed tomography (99mTc-ECD brain perfusion SPECT) is a beneficial modality for diagnosing dementia and identifying high-risk patients with mild cognitive impairment . The easy Z-score imaging system (eZIS) is one of the statistical analysis methods for automated diagnosis of brain perfusion SPECT images. It can be used to investigate the regional cerebral blood flow objectively and easily. SPECT with eZIS allows the identification of disease-specific patterns of regional cerebral blood flow in a three-dimensional brain magnetic resonance image, with the influence of age-related physiological regional cerebral blood flow changes avoided through normalization of data for each patient based on age-matched database for normal brains. However, there are few reports on the relationship between 99mTc-ECD brain perfusion SPECT with eZIS and the prognosis of patients with AF and dementia. The aim of this study was to evaluate the prognostic value of brain perfusion using 99mTc-ECD SPECT with eZIS in patients with AF and dementia.
Materials and methods
Assessment of AF
A 12-lead resting electrocardiogram recording (ECG-1450; Fukuda Denshi Co, Ltd., Tokyo, Japan) was performed in the study population. The electrocardiogram data were interpreted by cardiologists. This study’s inclusion criterion was an electrocardiographic documentation of AF, and the patients in this study were diagnosed with chronic AF (n = 117, 69%) or paroxysmal AF (n = 53, 31%) by cardiologists prior to undergoing 99mTc-ECD brain perfusion SPECT. The CHADS2 score has been proposed and validated as a straightforward and practical stratification of stroke risk in patients with AF . We retrospectively calculated the CHADS2 score for each patient by using the medical history data obtained through medical records.
Assessment of cognitive function
A psychological and psychosocial test, the Mini-Mental State Examination was administered to the study population to evaluate cognitive function, such as attention, semantic memory, visuospatial skills, and executive function . A score of 27 or under on the Mini-Mental State Examination was defined as dementia with mild cognitive impairment. The Mini-Mental State Examination was administered by neurologists and psychiatrists at our facility prior to performing the 99mTc-ECD brain perfusion SPECT.
Echocardiographic images were obtained from the parasternal window for the evaluation of the left ventricular function (Vivid E9device; GE Vingmed, Horten, Norway). The left ventricular ejection fraction (LVEF) was calculated using the Teichholz formula .
99mTc-ECD SPECT protocol
Before tracer administration, all subjects were laid in a supine position in a quiet room with dimmed light, with their eyes closed. Patients were injected with 99mTc-ECD (600 MBq) while they were awake. Ten minutes after radiotracer injection, SPECT images were acquired using a dual-head gamma camera (Infinia, GE Healthcare, Buckinghamshire, UK) equipped with low-energy high-resolution collimators. Images were acquired with each head rotating 180° in 72 steps, at 21 s/step, and were reconstructed with a Butterworth filter (cut-off, 0.55 cycle/cm; power, 10) and displayed in a 128 × 128 matrix. Scatter correction and attenuation correction were not performed.
Quantitation of brain SPECT images
Assessment of the clinical outcome
The endpoint was defined as the occurrence of major adverse cardiac events (MACE) including cardiac death (death caused by heart failure [HF], acute myocardial infarction, lethal ventricular arrhythmias, or other definitive cardiac disorders), cardiovascular events (acute myocardial infarction or unstable angina), severe HF requiring hospitalization, or stroke after undergoing the 99mTc-ECD brain perfusion SPECT. Only the initial event was counted, even if patients experienced several cardiac events during follow-up. The event data were retrospectively gathered from the patients’ medical records, including in-patient and out-patient medical records.
Data are expressed as the average ± standard deviation of the continuous variables. Continuous variables of patients with and without events were compared using the Mann-Whitney U test, and the categorical data were analyzed using the chi-square test. Variables including sex, age, and other factors which were significant (p value < 0.05) from univariable Cox regression were included in a multivariable Cox regression model to evaluate factors independently associated with future occurrence of MACE. To evaluate the clinical importance of Z-scores of the temporo-parieto-occipital lobe area, all patients were divided into 2 groups based on their Z-scores of the temporo-parieto-occipital lobe area. Each cut-off value was determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) analysis based on MACE occurrences. The proportion of event-free patients was estimated using the Kaplan-Meier method and compared with the high and low Z-scores of the temporo-parieto-occipital lobe groups by using the log-rank test. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using StatMate IV software version 4.01 (Advanced Technology for Medicine and Science, Tokyo, Japan).
Characteristics of all patients with or without MACE
Total (n = 170, %)
MACE (n = 62, %)
No MACE (n = 108, %)
81 ± 9
82 ± 10
81 ± 10
Obesity (BMI ≥ 25kg/m2)
22.3 ± 3.9
21.4 ± 3.8
22.9 ± 3.9
CKD (eGFR < 60mL/min/1.73m2)
Duration of AF (days)
1339 ± 1400
1262 ± 1368
1384 ± 1423
2.0 ± 1.0
2.5 ± 1.0
1.7 ± 0.9
22.7 ± 4.0
21.7 ± 4.1
23.2 ± 3.9
64.3 ± 12.1
63.0 ± 13.7
65.1 ± 11.1
4.0 ± 0.8
4.1 ± 0.8
4.0 ± 0.8
2.1 ± 1.9
2.6 ± 2.3
1.8 ± 1.5
203.4 ± 332.7
326.7 ± 491.0
132.6 ± 153.4
Z-score of Frontal lobe
2.05 ± 0.68
2.03 ± 0.72
2.05 ± 0.67
1.41 ± 0.54
1.59 ± 0.52
1.31 ± 0.53
Univariate and multivariable analysis for the occurrence of MACE
Age (> 75 years)
BMI (> 25 kg/m2)
CKD (eGFR < 60 mL/min/1.73 m2)
CHADS2 score (≥ 3)
MMSE score (< 23)
D-dimer (> 1.5 μg/mL)
BNP (> 100 pg/mL)
In the present study of patients with AF and dementia, we demonstrated the prognostic value of 99mTc-ECD brain perfusion SPECT, which is generally used for risk assessment in patients with dementia. Our findings demonstrated that the higher Z-score of the temporo-parieto-occipital lobe were associated with an increase in MACE events.
Patients with AF and dementia
The number of AF patients in the USA is about 2.3 million, and the numbers are increasing. It is predicted that more than half of patients over 80 years old will have AF in the USA . It was reported that the prevalence of cognitive disorder increases with age, increasing 5% of patients in their 70s to nearly 40% of that in 90s . By 2040 over 80 million people are expected to have cognitive disorder worldwide [13, 14]. Furthermore, recent data has emerged demonstrating an association between AF and dementia progression . Therefore, given the high-risk nature of AF and its relationship to dementia, prediction of future cardiac risk by using a non-invasive imaging method is essential. Several prior investigations have highlighted the mechanisms responsible for the association between AF and dementia [16, 17, 18, 19]. Cerebral microbleeds increase with age, and anticoagulation and microbleeds are associated with dementia [20, 21]. Cerebral hypoperfusion during AF may contribute to dementia. Decreased diastolic cerebral perfusion has also been associated with AF, and the irregular ventricular contraction during AF affects preload and cardiac output, which may result in a decreased mean cerebral flow [22, 23]. Therefore, evaluation of cerebral flow in AF patients by using 99mTc-ECD brain perfusion SPECT may serve not only for the diagnosis of dementia types and their severity but also as a measurement of the body’s circulation due to AF.
Prognostic value of 99mTc-ECD brain perfusion SPECT in patients with AF and dementia
In the current study, the Z-score of the temporo-parieto-occipital lobe area showed a significant association with cardiac events based on multivariable analysis. It has been reported that the temporo-parieto-occipital lobe brain areas control cognitive function . Therefore, the low accumulation of 99mTc-ECD in these areas by using 99mTc-ECD brain SPECT can evaluate the severity of dementia . The current study suggested that the accumulation of 99mTc-ECD in the temporo-parieto-occipital lobe areas may be a prognostic indicator for cardiac MACE. However, there was no significant difference in the accumulation of 99mTc-ECD in the frontal lobe area between patients with and without MACE. Therefore, the low accumulation of 99mTc-ECD in the frontal lobe area may indicate average brain perfusion due to AF. Patients with AF underlying coronary vascular/microvascular dysfunction have cerebral perfusion dysfunction . These patients are more likely to develop HF, both systolic and diastolic, which serves as a distinct mechanism underlying reduced cerebral perfusion . It is speculated that decreased perfusion of the temporo-parieto-occipital lobe area produced by AF results in a poor prognosis. In addition to the specific risks of AF, as dementia worsens, medication compliance, mental state, and activity worsen. This may lead to a poor prognosis in cardiovascular disease.
This study has several limitations. The number of patients was relatively small. However, our results clearly demonstrated that higher Z-scores of the temporo-parieto-occipital lobe area were significantly associated with MACE events. Although cerebral infarction or brain atrophy could influence the Z-score, we have not performed brain MRI for all the patients in the current study. While the Z-score could be overestimated in VD patients, we observed that the Z-scores of the temporal-occipital-parietal lobe in AD patients were higher than those of VD patients (p = 0.0132). A further limitation was that this study retrospectively analyzed the 99mTc-ECD brain perfusion SPECT data and outcomes from patients with AF and dementia. Therefore, the outcome review of medical records may have been incomplete. The prognostic impact on each etiology of dementia was not evaluated adequately due to the small sample size. Future prospective studies of large populations are required to confirm the prognostic value of Z-scores of the temporo-parieto-occipital lobe area in patients with AF and dementia.
This study demonstrated that the decreased cerebral blood flow in the temporo-parieto-occipital lobe measured by 99mTc-ECD brain perfusion SPECT could be a potential prognostic value in patients with both AF and dementia.
We are grateful to the radiology technologists Mr. Tadashi Kokubo, Mr. Kazuhiro Tachiki, Mr. Nobutomo Ishii, and Mr. Takushi Okubo for their technical assistance in the administration of 99mTc-ECD brain perfusion SPECT.
All authors made substantial contributions to the conception and design of the work, data analysis and interpretation of data. HH, YH, YO, and KY interpreted the data. HH performed the statistical analyses and drafted the manuscript. RN, SM, and TI reviewed and revised the manuscript. All authors provided final approval of the version submitted for publication.
Ethics approval and consent to participate
The institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived (M17307).
Consent for publication
A poster on this study was presented at the annual congress of the European Association of Nuclear Medicine, October 12–16, 2019 in Barcelona, Spain. The abstract was published in the European Journal of Nuclear Medicine and Molecular Imaging (2019) 46 (Suppl 1): S1–S952.
Takanori Ikeda has received grant support through his institution from Daiichi Sankyo, Bristol-Myers Squibb, and Boehringer Ingelheim, as well as honoraria for lectures from Bayer Healthcare, Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Tanabe-Mitsubishi, and Ono Pharmaceutical. Regarding this study, all authors declare that there is no potential conflict of interest.
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